PDF(Pubmed)
Abstract：
Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.
摘要：
次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖基转移酶活性的抑制减少了DNA和RNA合成所需的6-氧代和6-氨基嘌呤核苷单磷酸。导致细胞生长减少。因此,这种酶的抑制剂有可能控制感染，由恶性疟原虫和间日疟原虫引起，布鲁氏锥虫,结核分枝杆菌,和幽门螺杆菌。此处合成的五种化合物含有嘌呤碱基，其通过脯氨酸醇基团与一个或两个膦酸酯基团共价连接，其Ki值范围为3nM至>10μM，取决于抑制剂的结构和酶的生物来源。X射线晶体结构表明,关于绑定，这些含脯氨酸醇的抑制剂刺激了酶中活性位点环的运动。针对细胞培养中的TBr，前药表现出10μM的EC50。因此，这些化合物是进一步开发的优秀候选药物，作为抗感染性疾病的药物，也是潜在的抗癌剂。
